Evolution of simple repeats in DNA and their relation to human disease.
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Animals↗
Biomedical subjects
P Djian
Publications and source records attributed to P Djian.
Inability of keratinocytes lacking their specific transglutaminase to form cross-linked envelopes: absence of envelopes as a simple diagnostic test for lamellar ichthyosis.
Epidermal keratinocytes, late in their terminal differentiation, form cross-linked envelopes resistant to ionic detergent and reducing agent. Because the cross-linking process is catalyzed by the keratinocyte transglutaminase, the absence of active transglutaminase should result in failure of the keratinocyte to form a cross-linked envelope. Three keratinocyte strains bearing mutations in the keratinocyte transglutaminase were examined: two contained no detectable transglutaminase mRNA and none contained active enzyme. All three were unable to form cross-linked envelopes, either spontaneously in stratified cultures or upon induction with Ca2+. Although stratum corneum of normal humans and scales from patients with different ichthyotic diseases contain cross-linked envelopes, those from patients with transglutaminase-negative lamellar ichthyosis do not. Therefore, the disease due to the absence of transglutaminase may be readily distinguished from other ichthyotic disease by a simple test for cross-linked envelopes.
Cell Count↗
Transglutaminase action imitates Huntington's disease: selective polymerization of Huntingtin containing expanded polyglutamine.
Different proteins bearing polyglutamine of excessive length are lethal to neurons and cause human disease of the central nervous system. In parts of the brain affected by Huntington's disease, the amount of the huntingtin with expanded polyglutamine is reduced and there appear huntingtin-containing polymers of larger molecular weight. We show here that huntingtin is a substrate of transglutaminase in vitro and that the rate constant of the reaction increases with length of the polyglutamine over a range of an order of magnitude. As a result, huntingtin with expanded polyglutamine is preferentially incorporated into polymers. Both disappearance of the huntingtin with expanded polyglutamine and its replacement by polymeric forms are prevented by inhibitors of transglutaminase. The effect of transglutaminase therefore duplicates the changes in the affected parts of the brain.
Adolescent↗
Transglutaminase as the agent of neurodegenerative diseases due to polyglutamine expansion.
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Brain↗
The involucrin gene of the tree shrew: recent repeat additions and the relocation of cysteine codons.
The coding region of the involucrin gene of Tupaia glis has been cloned and sequenced. It resembles the involucrin coding region of other non-anthropoid mammals in possessing a segment of related, short tandem repeats at a defined location, but in Tupaia, there has been recent serial duplication of a repeat into which a cysteine codon had earlier been introduced. As a result of the duplication, there is a total of as many as six cysteine codons in the segment of repeats, a number larger than for any other species yet examined. In Ratttus there has been a comparable but independent addition of cysteine codons, and both Tupaia and Rattus have eliminated an otherwise conserved cysteine codon 75 located close to but outside the segment of repeats. In Tupaia, this elimination probably occurred by gene conversion. Also independently, the gene of Canis has added cysteine codons to the segment of repeats but has not yet lost cysteine 75. It is proposed that the gain and the loss of cysteine codons are parts of a multi-stage program of cysteine relocation.
Animals↗
Id3 prevents differentiation of preadipose cells.
We have studied the expression of the Id1, Id2, and Id3 genes during adipose differentiation of 3T3-F442A cells. All three Id mRNAs are present in preadipose cells, but the mRNA for Id3 is the most abundant. All three Id mRNAs sharply decline in the course of adipose differentiation, and their virtual disappearance precedes differentiation. The decrease in Id2 and Id3 is associated with adipose differentiation rather than with growth arrest since it is not observed in 3T3-C2 cells, a fibroblast line with a very low susceptibility to adipose conversion. The decline in Id2 and Id3 mRNAs is associated with a reduced transcription rate of the two genes. Id1 mRNA is reduced in amount during adipose conversion of 3T3-F442A cells, but the decrease is also observed in resting 3T3-C2 cells and is associated with very little decrease in transcription of the gene. Addition of fresh serum reactivates Id3 gene expression in quiescent 3T3-C2 cells but not in adipose 3T3-F442A cells. Stably transformed preadipose cells expressing an Id3 cDNA under the control of a viral promoter are virtually unable to differentiate. We postulate that the Id3 protein is a negative regulator of fat cell formation and presumably acts by preventing an as yet unidentified basic helix-loop-helix protein from activating the program of differentiation.
3T3 Cells↗
Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system.
Many proteins contain reiterated glutamine residues, but polyglutamine of excessive length may result in human disease by conferring new properties on the protein containing it. One established property of a glutamine residue, depending on the nature of the flanking residues, is its ability to act as an amine acceptor in a transglutaminase-catalyzed reaction and to make a glutamyl-lysine cross-link with a neighboring polypeptide. To learn whether glutamine repeats can act as amine acceptors, we have made peptides with variable lengths of polyglutamine flanked by the adjacent amino acid residues in the proteins associated with spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (SCA3), or dentato-rubral pallidoluysian atrophy (DRPLA) or those residues adjacent to the preferred cross-linking site of involucrin, or solely by arginine residues. The polyglutamine was found to confer excellent substrate properties on any soluble peptide; under optimal conditions, virtually all the glutamine residues acted as amine acceptors in the reaction with glycine ethyl-ester, and lengthening the sequence of polyglutamine increased the reactivity of each glutamine residue. In the presence of transglutaminase, peptides containing polyglutamine formed insoluble aggregates with the proteins of brain extracts and these aggregates contained glutamyl-lysine cross-links. Repeated glutamine residues exposed on the surface of a neuronal protein should form cross-linked aggregates in the presence of any transglutaminase activated by the presence of Ca2+.
Amino Acid Sequence↗
Codon repeats in genes associated with human diseases: fewer repeats in the genes of nonhuman primates and nucleotide substitutions concentrated at the sites of reiteration.
Five human diseases are due to an excessive number of CAG repeats in the coding regions of five different genes. We have analyzed the repeat regions in four of these genes from nonhuman primates, which are not known to suffer from the diseases. These primates have CAG repeats at the same sites as in human alleles, and there is similar polymorphism of repeat number, but this number is smaller than in the human genes. In some of the genes, the segment of poly(CAG) has expanded in nonhuman primates, but the process has advanced further in the human lineage than in other primate lineages, thereby predisposing to diseases of CAG reiteration. Adjacent to stretches of homogeneous present-day codon repeats, previously existing codons of the same kind have undergone nucleotide substitutions with high frequency. Where these lead to amino acid substitutions, the effect will be to reduce the length of the original homopolymeric stretch in the protein.
Animals↗
Tibial tunnel enlargement after anterior cruciate ligament reconstruction by autogenous bone-patellar tendon-bone graft.
This retrospective study was designed to evaluate changes in the diameter of the tibial tunnel over time following the reconstruction of the anterior cruciate ligament (ACL) with a bone-patellar tendon-bone autograft in 44 patients. The changes in the geometry of the bone tunnels were measured radiographically during the immediate postoperative period and at time intervals between 3 and 36 months after surgery. The dimensions at 1 year were correlated with the 1-year clinical results. The distance between the sclerotic margins of the tibial tunnel was measured at the distal tunnel exit on the medial tibial cortex, in the middle of the tunnel, and proximally at the level of the joint line. The dimensions were calculated by using a magnification factor determined by reference to the interference screw of known diameter located within the tunnel. The position of the centre of the tibial tunnel with regard to Blumensaat's line was also measured. The average tunnel diameter at the proximal tibial exit increased from 12 +/- 1.9 mm (mean +/- standard deviation) postoperatively to 14 +/- 2.2 mm at 3 months. The average proximal tunnel diameter did not significantly change from 3 months to 2 years, and then decreased to 13 +/- 2.4 mm at 3 years. At 1 year, most of the patterns of osteolysis were of the cone type (57%), followed by the cavity type (40%) and line type (3%). The degree of osteolysis was not related to the tibial tunnel position with respect to Blumensaat's line. There was no correlation between the changes in tunnel diameter and either the IKDC score or the residual joint laxity measured by a KT-100 arthrometer. The aetiology of tunnel enlargement is currently unknown. Possible factors responsible for bone resorption include micromotion of the graft relative to the tunnel wall, leading to an inflammatory response in the tunnel, or stress shielding of the tunnel wall proximal to the interference screw.
Adolescent↗
The involucrin gene and hominoid relationships.
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Animals↗
Origin of the polymorphism of the involucrin gene in Asians.
The involucrin gene, encoding a protein of the terminally differentiated keratinocyte, is polymorphic in the human. There is polymorphism of marker nucleotides a two positions in the coding region, and there are over eight polymorphic forms based on the number and kind of 10-codon tandem repeats in that part of the coding region most recently added in the human lineage. The involucrin alleles of Caucasians and Africans differ in both nucleotides and repeat patterns. We show that the involucrin alleles of East Asians (Chinese and Japanese) can be divided into two populations according to whether they possess the two marker nucleotides typical of Africans or Caucasians. The Asian population bearing Caucasian-type marker nucleotides has repeat patterns similar to those of Caucasians, whereas Asians bearing African-type marker nucleotides have repeat patterns that resemble those of Africans more than those of Caucasians. The existence of two populations of East Asian involucrin alleles gives support for the existence of a Eurasian stem lineage from which Caucasians and a part of the Asian population originated.
Alleles↗
Roentgenographic and magnetic resonance imaging of anterior cruciate reconstruction using a patellar tendon graft--correlations with physical findings.
The purpose of this study was to evaluate the influence of the graft positioning on the clinical outcome and magnetic resonance imaging (MRI) signal of the graft following anterior cruciate ligament (ACL) reconstruction using the central one-third of the patellar tendon. Twenty-two patients with a chronic anterior instability underwent a modified Marshall-MacIntosh procedure, while 27 with a subacute torn ACL had an ACL reconstruction using a free bone-patellar tendon-bone graft. The patients were retrospectively reviewed with a 1.8-year average follow-up (1-3 years). The clinical result was evaluated through the comparative range of motion and the residual laxity as measured with the KT 1,000 arthrometer. The roentgenographic analysis was performed from anteroposterior (AP) and mediolateral (ML) views, made first on one-leg standing with the knee at 30 degrees of flexion, and secondly at "zero" extension with active quadriceps contraction. Lines were drawn to visualise the location of the tibial and femoral tunnels in relation to the tibial plateaus and the intercondylar roof represented by Blumensaat's line. The analysis of the lateral MRI views of the graft allowed discrimination between homogenous and heterogenous graft signals. On lateral roentgenograms of normal knees, it was found that Blumensaat's line crossed the surface of the medial tibial plateau at 30% +/- 9% of its sagittal width (20%-40% range), demonstrating the variability of intercondylar roof inclination. The range of motion was normal in 34 patients (group I), 9 patients had a flexion deficit (group II), and 6 exhibited an extension deficit (group III). The residual laxity was similar in each group (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Anterior Cruciate Ligament↗
Recent advances in adult hip joint surgery.
This article is a summary of the information published in the field of hip surgery in adults over the past year. It reviews the epidemiology and economic aspects of total hip replacement, which dominates adult hip surgery, and examines the long-term results and complications that occur with both cemented and uncemented arthroplasty of the hip. Aseptic loosening is a major problem in the long-term outcome of total hip replacement. Wear of the bearings with production of particulate debris induces a local inflammatory response, activating the bone resorbing cells. Accordingly, revision surgery has become a frequent procedure that raises difficult problems. Strategy, methods, implant design, grafting, and indication for cemented or noncemented total hip replacements are discussed.
Adult↗
[Radiologic and MRI evaluation of intra-articular ligamentoplasty using a patellar tendon. Correlations with anatomical results].
INTRODUCTION: the purpose of this study was to evaluate the influence of the graft positioning on the clinical outcome and MRI signal of the graft as well, following ACL reconstruction using the central one-third of the patellar tendon. MATERIAL AND METHODS: twenty one patients having a chronic anterior instability sustained a modified Marshall-Mac Intosh procedure, while 15 having a subacute torn ACL had an ACL reconstruction using a free bone-patellar tendon-bone graft. The patients were retrospectively reviewed with a 1.8 year average follow-up (1-3 years). The clinical result was evaluated through the comparative range of motion, the residual laxity as measured with the KT 1000 arthrometer, and the pivot shift test. The roentgenographic analysis was performed from AP and ML views, made first on one-leg standing with the knee at 30 degrees of flexion, and then in "zero" extension with active quadriceps contraction. Lines were drawn to visualise the location of the tibial and femoral tunnels in relation to the tibial plateaus and the roof of the intercondylar notch represented by the Blumensaat line. The analysis of the AP IRM views of the graft allowed to discriminate between homogeneous and heterogeneous graft signals. RESULTS: on lateral roentgenograms of normal knees it was found that the Blumensaat line crossed the surface of the medial tibial plateau at its anterior third, at 30 +/- 9 per cent (20-40 per cent range), demonstrating the variability of the intercondylar roof inclination. The range of motion was normal in 22 patients (group 1), 8 patients had a flexion deficit (group II), and 6 exhibited an extension deficit (group III). The residual laxity was similar in each group (p > 0.05). When comparing group III to group I, patients from group III had a tibial tunnel significantly more anterior with regard to the Blumensaat line (p < 0.02). In group III, all patients exhibited an heterogeneous MRI graft signal (p < 0.05), and the angle between the intraarticular part of the graft and the tibial tunnel was higher (p < 0.001). These findings were not observed in group II where the location only of the femoral tunnel seemed to influence the flexion deficit (p > 0.05). DISCUSSION AND CONCLUSION: this study demonstrated that the location of the tibial tunnel with regard to the roof of the intercondylar notch, when the knee is in "zero" extension, was the most relevant parameter controlling the extension deficit resulting from a graft impingement. No relation was found between the tibial tunnel location with regard to the tibial plateaus and the mobility deficit. Graft impingement also was always associated with an heterogenous graft MRI signal. CLINICAL RELEVANCE: when reconstructing the ACL care must be taken when inserting the K-wire aimed to guide the tibial drill, to obtain a proper position with regard to the roof of the intercondylar notch. The K-wire location must be checked in "zero" extension. Intra-operative X-rays may help.
Anterior Cruciate Ligament↗
[Radiological changes in uncemented acetabular components. Apropos of 77 hybrid total hip prostheses reviewed with a mean follow-up of 3.5 years].
Seventy-seven total hip arthroplasty procedures performed between 1982 and 1989 for osteoarthritis by the same surgeon using a cementless acetabular component were reviewed retrospectively after a mean follow-up of 3.5 years. Clinical outcomes were similar to those seen with cemented implants. Roentgenographic analysis of acetabular position detected migration of 19 implants (25%). Actuarial survival analysis showed that the migration-free survival rate of acetabular components was 74.5% nine years after insertion. Bony consistency of the acetabulum after reaming was the only factor that significantly influenced the likelihood of acetabular component migration. Increased acetabular density after previous conservative hip surgery was associated with a significant reduction in the risk of migration (p = 0.003). Because anchorage quality was not predictable, we discontinued use of cementless acetabular components.
Acetabulum↗
[Pubalgia. A syndrome in of sport injury, corresponding to locoregional pathology].
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Athletic Injuries↗
The involucrin genes of the mouse and the rat: study of their shared repeats.
The involucrin genes of the mouse (Mus musculus) and the rat (Rattus norvegicus) have been cloned and sequenced. The coding region of each gene contains, at site P, a segment of repeats homologous to that of other nonanthropoid mammals. In contrast to the repeats of species belonging to different mammalian orders, many individual repeats of the mouse and the rat can be matched. Both before and after the divergence of the two species, these repeats have been the site of systematic alterations in nucleotide sequence. One of the alterations is the correction of nucleotides of one repeat by those of another. Corrected nucleotides may be closely linked to flanking nucleotides that are uncorrected; the systematic correction process therefore appears to be due to gene conversion. There is a stretch of 18 reiterated CAGs in the segment of repeats of the Mus gene; most of these reiterations were introduced recently, supporting the idea that the gene was generated originally from poly CAG. An antiserum to a synthetic peptide encoded by the segment of repeats of the Mus gene reveals differentiation-specific expression of the gene in the epidermis.
Animals↗
[Principles and value of isokinetic evaluation in ruptures of the anterior cruciate ligament].
Isokinetic muscular evaluation allows to appreciate the knee joint functional patterns in conditions close to sports activities. Analyzing bilateral symmetry and agonist/antagonist ratios of the lower extremity, this method is a useful index for the objective evaluation of ligament-deficient knees. 106 patients with a chronic ACL deficient knee sustained a presurgery isokinetic evaluation. 94 patients had a post-operative evaluation and 13 a pre and post-surgery evaluation. All patients were simultaneously evaluated by clinical examination and measures of instrumental knee laxity (KT 1000). Results showed that isokinetic performance was not correlated to the objective laxity as measured with the KT 1000 but was correlated to 1) the type of laxity (i.e. associated postero-lateral laxity), 2) the functional level of activity, and 3) the time of disability. Best functional results were obtained in patients whose injured knee hamstring/quadriceps (H/Q) ratio was close to the uninjured knee H/Q ratio. The mean quadriceps deficit was over 15 per cent for 75 per cent of the patients one year after surgery, and for 50 per cent of the patients after two years. The quadriceps deficit was not parallel to the length of the autograft taken from the extensor mechanism. Isokinetic evaluation is a guideline for rehabilitation allowing specific strengthening of the weaker muscular groups.
Anterior Cruciate Ligament↗